Bipolar4LifeSupport

Mental Health by the Numbers:
Prevalence of Mental Illness
Approximately 1 in 5 adults in the U.S.—43.7 million, or 18.6%—experiences mental illness in a given year.1
Approximately 1 in 25 adults in the U.S.—13.6 million, or 4.1%—experiences a serious mental illness in a given year that substantially interferes with or limits one or more major life activities.2
Approximately 1 in 5 youth aged 13–18 (21.4%) experiences a severe mental disorder in a given year. For children aged 8–15, the estimate is 13%.3
1.1% of adults in the U.S. live with schizophrenia.4
2.6% of adults in the U.S. live with bipolar disorder.5
6.9% of adults in the U.S.—16 million—had at least one major depressive episode in the past year.6
18.1% of adults in the U.S. experienced an anxiety disorder such as posttraumatic stress disorder, obsessive-compulsive disorder and specific phobias.7
Among the 20.7 million adults in the U.S. who experienced a substance use disorder, 40.7%—8.4 million adults—had a co-occurring mental illness.8
Social Stats
An estimated 26% of homeless adults staying in shelters live with serious mental illness and an estimated 46% live with severe mental illness and/or substance use disorders.9
Approximately 20% of state prisoners and 21% of local jail prisoners have “a recent history” of a mental health condition.10
70% of youth in juvenile justice systems have at least one mental health condition and at least 20% live with a serious mental illness.11
Only 41% of adults in the U.S. with a mental health condition received mental health services in the past year. Among adults with a serious mental illness, 62.9% received mental health services in the past year.8
Just over half (50.6%) of children aged 8-15 received mental health services in the previous year.12
African Americans and Hispanic Americans used mental health services at about one-half the rate of Caucasian
Americans in the past year and Asian Americans at about one-third the rate.13
Half of all chronic mental illness begins by age 14; three-quarters by age 24. Despite effective treatment, there are long delays—sometimes decades—between the first appearance of symptoms and when people get help.14
Consequences of Lack of Treatment
Serious mental illness costs America $193.2 billion in lost earnings per year.15
Mood disorders, including major depression, dysthymic disorder and bipolar disorder, are the third most common cause of hospitalization in the U.S. for both youth and adults aged 18–44.16
Individuals living with serious mental illness face an increased risk of having chronic medical conditions.17
Adults in the U.S. living with serious mental illness die on average 25 years earlier than others, largely due to treatable medical conditions.18
Over one-third (37%) of students with a mental health condition age 14­–21 and older who are served by special education drop out—the highest dropout rate of any disability group.19
Suicide is the 10th leading cause of death in the U.S.,20
the 3rd leading cause of death for people aged 10–2421 and the 2nd leading cause of death for people aged 15–24.22
More than 90% of children who die by suicide have a mental health condition.23
Each day an estimated 18-22 veterans die by suicide.24

Bipolar disorder is a clinically challenging condition. In addition to the multiple mood states that patients can experience, the illness is frequently associated with multiple comorbid medical and psychiatric conditions. Bipolar disorder can best be understood as a family of related disorders that share core features of mood or affective variation, impulsivity, propensity toward substance abuse, and predisposition to other psychiatric conditions.1 Most patients who have bipolar disorder have a coexisting anxiety disorder.2 These include generalized anxiety disorder (GAD), social phobia, panic disorder, and PTSD.2Anxiety disorders, by themselves or in combination with a mood disorder, are associated with an increased risk of suicide and psychosocial dysfunction.
The prevalence of comorbid bipolar and anxiety disorders (with the exception of simple phobias) is high in youths. For example, it is at least twice as high as comorbid anxiety and disruptive behavior disorders. GAD and separation anxiety are the anxiety disorders most commonly associated with bipolar disorder. In children with type I bipolar disorder, comorbid anxiety predicted greater dysfunction, manifested by earlier onset of bipolar disorder and more frequent psychiatric hospitalizations.
A comorbid anxiety disorder in bipolar patients greatly complicates the presentation, the interpretation of symptoms, and the treatment of bipolar disorder, and it negatively alters the prognosis.

Anxiety disorders comorbid with bipolar disorder
Panic disorder. In the Epidemiologic Catchment Area (ECA) study of the early 1990s, 21% of patients with bipolar disorder had comorbid panic disorder. This is a 26-fold higher incidence than in the general population.3 Panic disorder and bipolar disorder may share a special relationship with each other. A study of bipolar probands and their siblings found that panic disorder travels with bipolar disorder exclusively and rarely occurs independently of bipolar disorder.4 This unique relationship may be mediated by a genetic predisposition that resides in chromosome 18.5

Obsessive-compulsive disorder (OCD). In both the ECA study and the more recent National Comorbidity Survey, the incidence of OCD was 10-fold greater in bipolar patients than the general population.2,6 The risk of OCD is greater in family members of bipolar probands, which suggests a familial or genetic association. However, episodic obsessive-compulsive symptoms may simply be a variant of how bipolar disorder is expressed and not a true comorbidity. Either way, the relationship between bipolar disorder and OCD frequently has its origins in childhood and yields a greater burden of anxiety symptoms.

Posttraumatic stress disorder. PTSD may have a special relationship with bipolar disorder because both mania and depression may be perceived as traumatic or because events in the course of the illness may increase the risk of severe traumatic events.7 Consequently, PTSD may be over 6 times more likely to occur in bipolar patients than in the general population.2 The co-occurrence of PTSD with bipolar disorder lowers quality of life, increases rapid cycling and suicide attempts, and reduces the likelihood of remaining well.8

Social anxiety. Despite frequent grandiose or expansive behavior during mania, most patients with bipolar disorder actually suffer from social phobia—a potential contributor to dysfunction in bipolar patients.2

Comorbidity and outcomes
The combined burden of bipolar and anxiety disorders nearly always has a deleterious effect on outcomes.9 Comorbid illness is associated with marked increases in symptom burden that includes greater risk of psychosis, earlier age at onset of psychiatric symptoms, worse treatment response and more treatment resistance, impaired quality of life, increased suicidal ideation and actions, and increased substance abuse.9 Whether the poor prognosis is due to an interaction between the two conditions or to the additive burden is unknown.

Accurate diagnosis of comorbid anxiety disorder and bipolar disorder is important. The cost of care increases when a bipolar patient is treated exclusively for anxiety because of a misdiagnosis. Once a dual diagnosis has been made, effective treatment may be challenging.

Treatment of anxiety disorders

Antidepressants. Serotonergic antidepressants have shown efficacy as acute and prophylactic treatment for all anxiety disorders and are considered first-line agents.10 This is generally true whether the serotonergic effect is alone, is associated with noradrenergic reuptake inhibition, or is obtained by reuptake or monoamine oxidase inhibition.11 Non-serotonergic antidepressants (specifically bupropion) do not appear to be particularly effective.
In bipolar patients, antidepressants have the potential to induce mania, destabilize the course of illness by increasing bouts of mania and depression, and induce a chronic depressive state.11 The risk of these complications is higher if the bipolar patient receives antidepressants during periods of euthymia or over long periods.11 Use of antidepressants specifically for anxiety in bipolar patients would be expected to be associated with more complications. This may account for the observation that pharmacological treatments of comorbidities, such as anxiety disorders, in bipolar patients are generally underused, whereas psychosocial services are used more frequently by patients with coexisting anxiety disorders.12

Antipsychotics. Second-line pharmacotherapy for anxiety becomes first line in bipolar patients with anxiety disorder. Specifically, studies of atypical antipsychotics such as quetiapine have shown that these agents reduce anxiety in social anxiety disorder and GAD.13 Although the patients recruited for these studies did not have a mood disorder, quetiapine monotherapy (300 to 600 mg/d) significantly reduced anxiety and depressive symptoms in patients with bipolar disorder.14 Quetiapine may be of questionable benefit in patients with PTSD. While open-label, uncontrolled studies support use of this agent for PTSD, there were more early discontinuations with quetiapine than with prazosin and, thus, long-term benefit was lost.15,16

At doses below 4 mg/d, risperidone does not appear to be helpful for the treatment of anxiety symptoms in patients with bipolar disorder.17 Augmentation of mood stabilizer treatment with risperidone was also ineffective.18

The olanzapine/fluoxetine combination is approved for the treatment of bipolar depression. It may be useful in the treatment of comorbid anxiety as well. However, olanzapine alone has minimal effect.19

Anticonvulsants. There are no randomized controlled trials that examine the use of anticonvulsants for the anxiety component in bipolar patients. However, anticonvulsants appear to have a small effect in reducing anxiety. In a small open-label study, more than 40% of patients with GAD (without mood disturbance) saw at least a 50% improvement in symptoms with valproate.20 Similarly, modest benefit was seen in a group of patients with PTSD who received divalproex in an open-label study.21 Unfortunately, when the effect size is small in open-label studies, it suggests that results of blinded studies are likely to be negative.

Alternative agents. Gabapentin has been shown to be effective for social phobia in a randomized placebo-controlled trial.22 This effect on anxiety is probably what underlies the early reports of gabapentin efficacy in bipolar disorder. The related anticonvulsant, pregabalin, is also useful in social phobia and GAD at higher doses (approximately 600 mg/d).23 These agents have not been studied in bipolar patients with anxiety but are probably safe to use in this patient population.

Benzodiazepines are clearly effective in many different types of anxiety disorders. However, their use is problematic, and these agents must be prescribed cautiously.

Nonpharmacological approaches. Psychotherapy may be the treatment of choice for patients with anxiety disorders in general. For example, CBT is as effective as medications in the acute management of panic disorder. Unlike medications, the effect lasts long after treatment has ended.24 However, there are no randomized controlled trials for psychotherapy in bipolar patients who have comorbid anxiety. Nonetheless, therapies such as CBT and relaxation training may be useful in bipolar patients.25

Summary
Anxiety disorders are commonly comorbid with bipolar disorder and are responsible for much of the morbidity associated with this condition. Treatment of anxiety can be a challenge, since the mainstay of treatment—serotonergic antidepressants—may adversely affect the course of bipolar disorder. Although other agents are available, there is a dearth of information on the outcomes of anxiety treatment for bipolar patients.
Clinicians generally must apply the results of studies performed in patients who have anxiety disorders without mood disturbance to their bipolar patients. This is a reasonable practice, although it is far from ideal. The field needs more high-quality research studies to define the best practice options in treating patients with comorbid anxiety and bipolar disorders.

Quite reasonably, patients with bipolar disorder want treatment that provides sustained relief from their illness without incurring serious side-effects. Functionally, this translates to the resumption of purpose and enjoyment. But of the numerous drugs available for the management of bipolar disorder, only lithium seems to truly stabilise mood.1 Its status as an effective prophylactic agent was convincingly reinstated by the findings of the randomised, open-label BALANCE trial,2 which corroborated empirical knowledge. The BALANCE investigators showed that lithium alone, or lithium plus valproate, are more likely to prevent relapse than valproate monotherapy, and prophylaxis with lithium monotherapy might be on a par with lithium plus valproate.

Hence, despite fluctuating popularity, lithium remains a first-line option for the treatment and prophylaxis of bipolar disorder in therapeutic guidelines.3 However, use of lithium in practice is limited by concerns about safety and adverse effects with long-term use.

Extending previous research that examined the short-term tolerability of lithium,4 in The LancetBrian Shine and colleagues5 have drawn on a large set of data to determine the long-term effects of lithium on renal and endocrine function. Data from 4678 patients were included in the study, of whom 2795 had their serum lithium measured more than once. Shine and colleagues’ findings show that lithium was associated with increased risk of stage three chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1·73m2; hazard ratio 1·93, 95% CI 1·76–2·12), hypothyroidism (thyrotropin activity >5·5 mU/L; 2·31, 2·05–2·60), and hypercalcaemia (1·43, 1·21–1·69).

These findings send a key message to clinicians to monitor lithium therapy closely from the outset. Both thyroid hormone secretion and renal function can decline with long-term lithium use and can, in some cases, lead to hypothyroidism and stage three chronic kidney disease. Interestingly, these complications are more likely to occur in women than in men, and are detected early in the course of lithium treatment. In addition, long-term lithium therapy can also cause hypercalcaemia (ie, total plasma calcium concentration ≥2·6 mmol/L).

All adverse effects are more likely to occur when plasma lithium concentration is high. Therefore, patients receiving lithium therapy should have thyroid function, renal clearance, and blood calcium concentrations assessed carefully at the beginning of therapy and monitored closely thereafter. Shine and colleagues5 provide clear evidence of the potential risks associated with long-term lithium treatment. But because bipolar disorder typically emerges at a young age6 and requires lifelong treatment, these findings prompt the question: how can these hazards be navigated?

The answer is twofold. First, avoid sustained periods during which plasma lithium concentrations are high to diminish the risk of serious adverse effects. Second, all the parameters that need regular assessment, such as thyroid and renal function tests and plasma lithium and calcium concentrations, can be measured reliably and easily. However, the treatment of type I bipolar disorder, the subtype best suited to lithium therapy,7 is often complicated by comorbid anxiety and substance misuse. Furthermore, lithium’s therapeutic effect occurs at concentrations that can be toxic if maintained in the long term.8 These concerns reinforce a widely held view that lithium therapy is problematic. But all drugs are associated with side-effects, and long-term management often involves a risk–benefit analysis at some point in the treatment course; lithium is no exception.

Maintenance of lithium concentrations at the lower end of the therapeutic range (ie, 0·6 mmol/L) can reduce the adverse outcomes associated with lithium treatment. For plasma lithium concentrations to be high enough to be efficacious, but low enough to avoid toxicity, is a delicate balance. The simple pharmacokinetics of lithium in plasma offer some assistance, but the pharmacokinetics of lithium within the brain are more complex because the blood–brain barrier insulates the brain from rapid changes in plasma lithium concentration and facilitates its accumulation in neural tissues, which can be neurotoxic.9

The movement of lithium between plasma, cerebrospinal fluid, and brain tissue is not fully understood, and future research will need to examine the effects of different doses and duration of lithium treatment on concentrations within these various compartments. For example, a low concentration of lithium in the plasma (0·2–0·4 mmol/L) has little effect on renal and thyroid function,10 and is achievable with alternate-day dosing.9

Lithium is without doubt the best treatment for many patients with bipolar disorder because it confers long-term mood stability and prophylaxis (figure). Lithium also reduces the risk of suicide11and is possibly neuroprotective.12 The dilemma of lithium therapy arises because, if poorly managed, lithium can compromise renal function, sometimes irreversibly, and severely disrupt endocrine homoeostasis—ultimately limiting its usefulness. Therefore, lithium therapy remains a challenge that will benefit from a better understanding of its therapeutic properties.

Figure

The Lithium Membrain by Anne Naylor
Lithium coursing through veins in the brain (blue) provides mood stability by acting as a membrane that prevents the effects of the various faces of the illness (circles) on the brain (neural networks).

Anne Naylor 2014
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I have received research funding from AstraZeneca, Eli Lilly, Organon, Pfizer, Servier, and Wyeth; am a speaker for AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; and a consultant for AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck, and Servier.